bims-oxygme 2025-04-06 papers

bims-oxygme

Biomed News

on Oxygen metabolism

Issue of 2025–04–06
seven papers selected by
Onurkan Karabulut, Berkeley City College

Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1α-Coordinated Cellular Adaptation to Graded Hypoxia.
Oxygen metabolism abnormalities and high-altitude cerebral edema.
Geographic Variation in Epigenetic Responses to Hypoxia in Deer Mice (Peromyscus maniculatus) Distributed Along an Elevational Gradient.
Identification and validation of hypoxia-responsive signature pathways in human cardiomyocytes.
Sucrose- and fat-related metabolic states influence the adaptation of the pulmonary lipid metabolism to hypoxia.
Torticollis and Hypoxia in a Febrile 3-Year-Old Girl.
Evaluation of Prognostic Findings in Newborns with Hypoxic Ischemic Encephalopathy: 5-Year Experience.

Research (Wash D C). 2025 ;8 0651

Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1α-Coordinated Cellular Adaptation to Graded Hypoxia.

Ping Wang, Xiao-Peng Zhang, Feng Liu, Wei Wang.

Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1α network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1α is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glycolysis, immunosuppression, angiogenesis, and necroptosis are orderly elicited in aggravating hypoxia. To avoid the excessive accumulation of lactic acid during glycolysis, HIF-1α induces monocarboxylate transporter and carbonic anhydrase 9 sequentially to export intracellular hydrogen ions, facilitating tumor cell survival. HIF-1α-induced miR-182 facilitates vascular endothelial growth factor production to promote angiogenesis under moderate hypoxia. The imbalance between accumulation and removal of lactic acid in severe hypoxia may result in acidosis and induce cell necroptosis. In addition, the deactivation of FIH results in the destabilization of HIF-1α in anoxia. Collectively, HIF-1α orchestrates the adaptation of tumor cells to hypoxia by selectively inducing its targets according to the severity of hypoxia. Our work may provide clues for tumor therapy by targeting the HIF-1 pathway.

DOI: https://doi.org/10.34133/research.0651
Front Immunol. 2025 ;16 1555910

Oxygen metabolism abnormalities and high-altitude cerebral edema.

Zhi Li, Jianping Zhang, Xiaoxia Zhang, Qiaoying Jin, Xingxing Zheng, Li Mo, Zejiao Da.

  Hypobaric hypoxia is widely recognized as a prominent risk factor for high-altitude cerebral edema (HACE), which contributes to the exacerbation of multiple pathological mechanisms, including oxidative stress, mitochondrial dysfunction, disruption of blood-;brain barrier integrity, neuroinflammation, and neuronal apoptosis. Among these mechanisms, abnormalities in oxygen metabolism, including hypoxia, oxidative stress, and mitochondrial dysfunction, play pivotal roles in the pathophysiology of HACE. In this review, our objective is to enhance our comprehension of the underlying molecular mechanisms implicated in HACE by investigating the potential involvement of oxygen metabolism. Addressing aberrations in oxygen metabolism holds promise for providing innovative therapeutic strategies for managing HACE.

Keywords:  high-altitude cerebral edema; hypobaric hypoxia; mitochondrial dysfunction; oxidative stress; oxygen metabolism

DOI:  https://doi.org/10.3389/fimmu.2025.1555910
Mol Ecol. 2025 Mar 28. e17752

Geographic Variation in Epigenetic Responses to Hypoxia in Deer Mice (Peromyscus maniculatus) Distributed Along an Elevational Gradient.

Dhriti Tandon, Shane Campbell-Staton, Zachary Cheviron, Bridgett M von Holdt.

  Lowland and highland Peromyscus maniculatus populations display divergent, locally adapted physiological phenotypes shaped by altitudinal differences in oxygen availability. Many physiological responses to hypoxia seem to have evolved in lowland ancestors to offset episodic and localised bouts of low internal oxygen availability. However, upon chronic hypoxia exposure at high elevation, these responses can lead to physiological complications. Therefore, highland ancestry is often associated with evolved hypoxia responses, particularly traits promoting tolerance of constant hypoxia. Environmentally induced DNA methylation can dynamically alter gene expression patterns, providing a proximate basis for phenotypic plasticity. Given each population's differential reliance on plasticity for hypoxia tolerance, we hypothesised that lowland mice have a more robust epigenetic response to hypoxia exposure, driving trait plasticity, than highland mice. Using DNA methylation data of tissues from the heart's left ventricle, we show that upon hypoxia exposure, lowland mice chemically modulate the epigenetic landscape to a greater extent than highland mice, especially at key hypoxia-relevant genes such as Egln3. This gene is a regulator of the gene Epas1 that is frequently targeted for positive selection at high elevation. We find higher methylation among wild highland mice at gene Egln3 compared to wild lowland mice, suggesting a shared epigenetic ancestral response to episodic and chronic hypoxia. These findings highlight each population's distinct reliance on molecular plasticity driven by their unique evolutionary histories.

Keywords:  DNA methylation; hypoxia; plasticity

DOI:  https://doi.org/10.1111/mec.17752
3 Biotech. 2025 Apr;15(4): 103

Identification and validation of hypoxia-responsive signature pathways in human cardiomyocytes.

Dolly Sharma, Karuna, Harshita Gupta, Avinash Gupta, Manisha Kumari, Rajeev Varshney, Ramesh C Meena.

  The present study was designed to investigate the effect of hypoxia (1% O2) for 24 h in human AC16 cells by analyzing alterations in the expression of cardiac markers and signature pathways using immunocytochemistry and next-generation sequencing respectively. The Gene set enrichment analysis and Cytoscape software were used for data analysis and visualization respectively. Sequencing data validation and functional characterization were done using flow cytometry, qRT-PCR, an antibody array, and immunoblotting. The result revealed that the expression levels of troponins decreased; however, the expression levels of VEGF-A and HIF-alpha increased under hypoxia compared with unexposed control. A total of 2120 genes corresponding to 457 gene sets were significantly altered, 153 of which were significantly upregulated and 304 of which were downregulated in hypoxic cardiomyocytes. The significantly altered gene sets corresponded to key cellular and molecular pathways, such as cardiac hypertrophy, transcription factors, microRNAs, mitochondrial abnormalities, RNA processing, cell cycle, and biological oxidation pathways. Thus, this analysis revealed multiple pathways associated with hypoxia which provides valuable insights into the molecular mechanisms underlying human cardiomyocytes, identifying potential targets for addressing cardiac illnesses induced by hypoxia.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-025-04271-z.

Keywords:  Cardiac markers; Cardiomyocytes; Cytoscape; GSEA; Hypoxia; Next-generation sequencing

DOI:  https://doi.org/10.1007/s13205-025-04271-z
Cell Tissue Res. 2025 Apr 01.

Sucrose- and fat-related metabolic states influence the adaptation of the pulmonary lipid metabolism to hypoxia.

Sophia Pankoke, Lea Gerling, Matthias Ochs, Christian Mühlfeld, Julia Schipke.

  Pulmonary surfactant is essential for lung function and consists mainly of lipids, almost half of which in adult mammals originate from de novo synthesis in alveolar epithelial type-2 (AE2) cells. Obesogenic nutrition and hypoxia coexist in obese patients with chronic lung diseases. This study tested the hypothesis that diet-induced obesity and chronic hypoxia alter lipid metabolism and thereby deteriorate surfactant homeostasis. Male C57BL/6N mice were fed control diet (4% fat, 6% sucrose; CD), high-sucrose diet (4% fat, 46% sucrose; HSD) or high-fat diet (35% fat, 7% sucrose; HFD). After 27 weeks, half of each diet group was exposed to hypoxia (13% O2, Hyp) for 3 weeks. After 30 weeks, lung mechanics were assessed, and the blood, livers, and lungs were analyzed. In CD-fed mice, hypoxia induced lung mechanical changes indicative of reduced elastic recoil properties, as well as smaller lamellar bodies (LBs) and higher composite body volumes, suggesting an increased surfactant precursor formation. HSD and HFD induced lipid accumulation in liver and AE2 cells. In HSD-Hyp and HFD-Hyp, LB volumes per alveolar surface area were elevated, indicating compensatory increases in intracellular surfactant pools which were absent in CD-Hyp. Additionally, hypoxia-related lung mechanics alterations were less pronounced in HSD-Hyp and HFD-Hyp. Lung proteome analysis revealed that only a few lipid metabolism-associated proteins were similarly regulated within diet groups under hypoxia, with the most prominent changes in sucrose-fed hypoxic animals. Thus, individual diet-related metabolic states specifically affect the adaptation of the pulmonary lipid metabolism and intracellular surfactant assembly to chronic hypoxia.

Keywords:  Dietary carbohydrates; Dietary fat; Lipid metabolism; Nutrition; Obesity; Proteomics; Pulmonary surfactant

DOI:  https://doi.org/10.1007/s00441-025-03968-0
Pediatr Rev. 2025 Apr 01. 46(4): 213-215

Torticollis and Hypoxia in a Febrile 3-Year-Old Girl.

Roselyn Appenteng, Lauren K Kahl.

DOI: https://doi.org/10.1542/pir.2023-006088
Ther Hypothermia Temp Manag. 2025 Mar 31.

Evaluation of Prognostic Findings in Newborns with Hypoxic Ischemic Encephalopathy: 5-Year Experience.

Ozlem Sahin, Derya Colak, Funda Yavanoglu Atay, Omer Guran, Ilke Mungan Akin.

  Hypoxic-ischemic encephalopathy (HIE) is a constellation of neurological signs as a result of hypoxia, hypercapnia, metabolic acidosis, and cerebral ischemia before birth. The aim was to evaluate risk factors, clinical and laboratory findings, and morbidity and mortality in neonates diagnosed with HIE who underwent therapeutic hypothermia (TH). Between January 2015 and December 2020, neonates diagnosed with HIE were evaluated in the neonatal intensive care unit. Risk factors, sociodemographic characteristics, degree of encephalopathy, clinical and laboratory findings, results of amplitude-integrated electroencephalography (aEEG), electroencephalography (EEG), magnetic resonance imaging (MRI) including diffusion weighted imaging (DWI) and cranial ultrasound (cUS), and mortality were retrospectively recorded. Of the 81 cases, we followed up with a diagnosis of HIE. When the patients were divided into groups and evaluated according to the Sarnat & Sarnat staging system, it was observed that 22 (27.2%) of the patients had mild HIE, 49 (60.5%) of the patients had moderate HIE, and 10 (12.3%) of the patients had severe HIE. The aEEG, EEG, DWI, and renal pathology of patients with seizures were statistically significantly higher than those of patients without seizures (p = 0.004, p = 0.002, p = 0.014, p = 0.025). MRI was performed in 66 patients within the first 7 days of life, and diffusional restriction was found in 22 of them. We found that DWI is superior to cUS in determining the severity of hypoxic injury and that renal involvement may be associated with poor neurodevelopmental outcomes. Due to the abnormal prognostic findings detected in infants with mild HIE, the existence of a standard definition of mild HIE that will determine the efficacy and reliability of therapeutic hypothermia will enable at risk infants to benefit from neuroprotective strategies.

Keywords:  Hypoxic ischemic encephalopathy; acute kidney injury; magnetic resonance imaging; neonate; therapeutic hypothermia

DOI:  https://doi.org/10.1089/ther.2025.0011